title: Role of Abl in airway hyperresponsiveness and airway remodeling.
abstract: BACKGROUND
  Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.
  
  
  METHODS
  To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.
  
  
  RESULTS
  The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma. Conditional knockout of Abl attenuated airway resistance, smooth muscle mass and staining of proliferating cell nuclear antigen in the airway of mice sensitized and challenged with ovalbumin. Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin. However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.
  
  
  CONCLUSIONS
  These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma. Our findings support the concept that Abl may be a novel target for the development of new therapy to treat asthma.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue MC-8, Albany, NY 12208, USA. tangd@mail.amc.edu.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Cleary
authors.forename: Ruping
authors.initials: R
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Dale D
authors.initials: DD
authors.lastname: Tang
mesh_terms: D056151:Airway Remodeling / Q000502:physiology*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D018793:Interleukin-13 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology*; D010047:Ovalbumin / Q000009:adverse effects; D010879:Piperazines / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D001549:Benzamides; D018932:Chemokine CCL2; D018793:Interleukin-13; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010047:Ovalbumin; D016315:Proto-Oncogene Proteins c-abl